Week 8 Flashcards
What are the functions of the kidneys?
- Filtration of plasma
- Resorption of water and electrolytes
- Blood pressure
- Production of erythropoietin: stimulates the production of red blood cells
- Production of Vitamin D
- Gluconeogenesis: creation of glucoses from smaller, noncarbon source
- Acid base balance
- Excretion of waste products
How many kidneys?
- which is lower
- which has longer renal vein
- preferred for donation
- right; bc of liver
- left
- left
Parts of a nehron
- glomerulus
- bowmans capsule
- PCT
- Loop of Henle
- DCT
- collecting duct
Types of nephrons
- location of glomerulus
- loop of henle
- peritubular capillaries
- cortical and juxtamedullary
- both in the cortex
- C: mostly in cortex, barely dips into the medulla; J: completely in the medulla
- C: does not have venule end; J: has venule end
Juxtaglomerular apparatus
- components
- podocytes
- granular cells that release renin
- macula densa with Na, Cl-
- Efferent and Afferent arterioles
- Medangial cells; phagocytic
Granular cells
- location
- make?
- type of cell
- Located on the afferent arterioles
- They contain vesicles, and inside are renin
- modified vascular smooth muscle cells of afferent arterioles
Mesangial cells
- what are they?
- phagocytic cells/ modified macrophage
Macula densa cells
- location
- what are they?
- job?
- junction of DCT and peak ascending arteriole limb
- modified epithelial cells
- transporters; have potassium, sodium, chloride transporters
Basic renal processes (4)
Filtration, secretion, reabsorption, excretion
Excretion versus secretion
- Excretion is what leaves the body– into urine
- Tubular secretion is released into tubular fluid
When cells of the renal tubules secrete the drug penicillin, is the drug being added to or removed from the bloodstream
What happens after?
- Secreted; the drug is being removed from blood stream and into the tubule fluid
- The substances can also be reabsorbed after secretion, depends on the substances on whether they are secreted or excreted
Why is it called reabsorption
- The second time being absorbed– first time is in the gut
- Those substances are absorbed first in the GI tract
what component of the filtration membrane damaged resulting in hematuria?
endothelial cells of the capillaries; usually the fenestrations
component of filtration membrane damaged resulting in proteinuria?
basement membrane; specifically heparin sulfate and glycoproteins
Student w/ hematuria 1 wk after pharyngitis w/ elevated BP , BUN, and serum creatinine. Positive for RBC casts and dysmorphic RBC in urine.
- what condition? why?
- cause
- key features?
- nephritic syndrome bc of the blood in the urine
- cross-reactivity between the Abs from streptococcus and the fenestrated glomerular cells so there is damage to the glomerular endothelial cells
- HTN, arguably oligouria, dysmorphic RBCs and casts found in urine.
56 yr old male with edema, weight gain, ascites, and S3 galllop. Serum showed elevated Na and lipids and low albumin
- condition. why?
- pahthophysiology behind edema and proteinuria?
- patho behind hyperlipidemia
- nephrotic syndrome; Bc of the edema and lots of proteins in the urine
- capillary walls have increased permeability to proteins
- when there’s low oncotic pressure liver is stimulated to produce more proteins and also loss of lipids in urine favors production of lipoproteins so lipids can bind to them. Liver does produce albumin as well but here we are talking abut the connection between the lipids/hyperlipidemia.
Nephritic syndrome
- pathogen
- features
- inflammation of the glomerulus damaging the fenestration in capillary endothelium
- Hematuria and RBC casts in urine
Nephrotic Syndrome
- loss of nephrin and negative charges on the glomerular filtration
- proeinuria, edenam hyperlipidemia
Units for GFR
- normal range
- mL/min OR L/hr OR L/day
- 80-120 mL/min
Formula to calculate GFR
clearance=urine concentration*volume of urine flow rate/ plasma concentration of substance
best substance to use to measure GFR?
- It cannot be secreted, reabsorbed, metabolize or synthesized but can be freely filtered
What directly determines GFR?
- what favors filtration?
- what opposes filtration?
- what can happen with tumor obstructing R ureter? Would anything happen to the L Kidney?
- glomerular capillary blood pressure
- fluid pressure in bowmans space (the fluid backing up as it funnels down) and osmotic pressure in capillary bc of protein left behind
- It would cause a decrease in filtration because it would increase the fluid pressure in bowmans capsule; L kidney would be unaffected
Renal blood flow
aorta -> renal a -> segmental a -> interlobar a -> arcuate a -> cortical radiate a -> afferent a -> glomerulus -> efferent a -> peritubular capillaries/vasa recta -> cortical radiate v -> arcuate v -> interlobar v -> renal v -> IVC
role of arterioles?
- controlled by?
- what happens if renal arteriole constricts?
- they constrict to modulate blood flow
- autonomic NS
- GFR decreases and there is more time for substances to be reabsorbed
How do we differentiate renal plasma flow from renal blood flow
- renal blood flow is the amt of blood that is delivered to kidneys and plasma is all the products that are removed except the protein content that’s still maintained in that plasma. So it’s a measurement of the protein being filtered.
How do you calculate renal blood flow if you are given renal plasma flow?
RBF = RPF x (1 - HCT)
What is the best substance used to measure renal plasma flow?
Paraimmunohepuric acid- it’s almost 100% excreted bc it’s freely filtered and secreted but not reabsorbed
define filtration fraction
GFR/ RBF
RPF, GFR, and FF during
- afferent arteriole constriction
- afferent arteriole dilation
- efferent arteriole constriction
- efferent arteriole dilation
- increased plasma protein concentration
- decreased plasma protein concentration
- obstruction of ureter
- R: decrease, G: decrease, FF: same
- R: increase, G: increase, FF: same
- R: decrease, G: increase, FF: increase
- R: increase, G: decrease, FF: decrease
- R: no change, G: decrease, FF: decrease
- R: no change, G: increase, FF: increase
- R: no change, G: decrease, FF: decrease
45 y/o f w/ hematuria and acute, colicky flank pain. H/o high doses of acetaminophen and aspirin. BP and temp normal. Positive for proteinuria.
- what dx?
- cause?
- • How much % of CO goes to kidney?
- renal papillary necrosis
- Using a lot of NSAIDs causes constriction of afferent arterioles leading to decreased renal blood flow–>ischemic injury to tip of Loop of Henle–>necrosis.
- 20-25%; Less than 10% of blood goes to peritubular capillaries, and by time blood reaches tip of loop of Henle (which is near renal papilla) the blood flow is less than 1%. So the tip of loop of Henle are at increased risk of injury d/t decreases in blood flow.
Glomerulotubular balance
- what does this help with?
refers to the phenomenon whereby sodium reabsorption in the proximal tubule varies in parallel with the filtered load, such that about two-thirds of the filtered sodium is reabsorbed even when GFR varies
- If there was an increase in GFR and the reabsorbed amt remained fixed, all the excess would not be reabsorbed and would be passed on to loop of Henle. But with glomerulotubular balance, the amount reabsorbed will also rise 20% so that the fractional reabsorption remains the same.
Autoregulation of RBF and GFR
- Pressure-induced stretch d/t increased blood pressure sensed by vascular smooth muscle–> causes the opening of Ca2+ channels. The influx of Ca2+ leads to the initiation of excitation-contraction coupling–> contraction of vascular smooth muscle and constriction of the blood vessel–>decreased blood flow–>decreased GFR
Tubuloglomerular feedback
- how does it happen?
- role of macula densa
- increase in salt and fluid
- how? GFR vs Na excretion?
- decrease in salt and fluid?
- regulation of GFR by the macula densa
- Macula densa is located at end of loop of Henle and it senses flow and salt concentration in the tubular lumen
- paracrine mediators (ATP/adenosine) released by the macula densa reduce GFR by binding to receptors on afferent arteriole smooth muscle leading to increased intracellular Ca2+ –> contraction of afferent arteriole smooth muscle–> reduces pressure and flow through the glomerular capillaries –>decreased GFR
- Adenosine binds to receptors on juxtaglomerular cells which increases intracellular calcium and reduces release of renin–>decreased renin reduces ATII and aldosterone levels–>allows kidneys to excrete more of the filtered sodium
- If there is decreased salt and fluid in tubular lumen, prostaglandins, NO are released to raise GFR
Renal Clearance– identify whether the substance X is filtered, reabsorbed or secreted when the when substance X…
- less than insulin clearance?
- more than insulin clearance?
- equal to insulin clearance?
- Cx < C insulin: more filtration and reabsorption
- Cx > C insulin: more filtration and more secretion
- Cx = C insulin: no drastic change in reabsorption or secretion
If there were a toxin that blocked renal tubule reabsorption but does not affect filtration; predict the short term effects on
- blood pressure
- glomerular capillary hydrostatic pressure
- net filtration pressure
• Blood pressure: Decreased BP because she’s not reabsorbing the substances (solutes or water). Salt and water is being lost which decreases the BP.
• Glomerular capillary hydrostatic pressure will decrease
- Net filtration pressure will decrease d/t decrease in hydrostatic pressure
Ions normally secreted into kidney
- K and H
Ions normally reabsorbed
NaHCO3, NaCl, H2O, Cl-, K+, Na+, Mg2+, Ca2+
dentify localization of the following transporters and channels in the apical and basolateral membranes of the early proximal tubule (PT)
a. Na+-glucose cotransporter b. Na+-Amino acid cotransporter
c. Na+-PO4 cotransporter
d. Na+-H+ exchanger-
e. Epithelial Ca2+ channels
f. Na+-K+ ATPase
g. Glucose transporter
h. Amino acid transporter
i. PO4 transporter
j. HCO3- transporter
k. Na+-Ca2+ exchanger
l. Ca2+-H+ ATPase
a. Na+-glucose cotransporter –> Apical
b. Na+-Amino acid cotransporter–> Apical
c. Na+-PO4 cotransporter–> Apical
d. Na+-H+ exchanger–> Apical
e. Epithelial Ca2+ channels–> Apical
f. Na+-K+ ATPase–> Basolateral
g. Glucose transporter–> Basolateral
h. Amino acid transporter–> Basolateral
i. PO4 transporter–> Basolateral
j. HCO3- transporter–> Basolateral
k. Na+-Ca2+ exchanger–> Basolateral
l. Ca2+-H+ ATPase–> Basolateral
Brief explanation of sodium reabsorption in the early PT cells
- Na+/K+ ATPase
- concentration gradient
- where are they moved after being put into cell
- First Na+/K+ ATPase pumps sodium into the blood which keeps intracellular [Na+] low –>. This creates a concentration gradient of sodium that helps facilitate transport of Na+ into the cell from the lumen side with Na+ cotransporters.–> Na+ movement across the apical membrane moves nutrients along with it such as glucose, amino acids, ad PO43-. These are then transported into the blood through the Glucose, PO4, and amino acid transporters on the basolateral side. And the sodium itself is pumped into the blood through Na/K ATPase.
How does Ca++ reabsorption happen in the PCT
- what transporter is used?
- concentration of Ca in cell
- how does it get into cell
- paracellular
- Ca+ is being pumped out into the blood by Ca2+/Na+ exchanger and Ca2+/H+ ATPase pump on the basolateral side —> This creates a low concentration gradient inside the cell —> Because of this gradient, Ca2+ is reabsorbed from the lumen through calcium channels
- Paracellular reabsorption of Ca2+ and Mg2+ also occurs due to the + charge in the lumen
How is ammonia formed from the glutamine in the early PT epithelial cells?
- what happens to the extra H?
- Glutamine is broken down into ammonia and alpha-ketoglutarate –> bicarb is formed from alpha-ketoglutarate, -> Bicarb enters the blood via bicarb transporters on the basolateral side and Ammonia is transported into the lumen through ammonia transporters
- The extra H+ that was given off in the conversion of Glutamine to ammonia is transported out of the cell via Na+/H+ exchanger on the apical side –> now with both ammonia and H+ moved into the lumen, they can recombine to make ammonium.
How does the early proximal cell create bicarb?
- where do the products go?
- Another reaction occuring in the cell is production of bicarb by carbonic anhydrase. This enzyme, remember, combines water and carbon dioxide to make the H+ bicarbcarbonic acidCO2+H2O buffer system
- Similar to the Glutamine pathway, the H+ ion goes into the lumen via Na/H exchanger on the apical side… and bicarb goes out into the blood via bicarb transporters on the basolateral side.
What are the substances reabsorbed most in the early PT?
- Sodium -> water
- Bicarbonate ions
- Ca2+
PTH effect on Early proximal Tubule
- Its’ role is to inhibit the sodium phosphate cotransporter on the apical side
Angiotensin II (ATII) effect on early proximal tubule
- Stimulates sodium-hydrogen exchanger on the apical side
- plays a role is sodium reabsorption (and water reabsorption) in the proximal tubule cells.
direct and indirect effects of carbonic anhydrase inhibitor in the early PT.
a. Direct: sodium entry into the early proximal convoluted tubule is blocked (because H+ production by CA is decreased… so there is less to exchange for Na+ on the apical side) –> This causes less resorption of water because you will pee out all of the Na+–> acts as a diuretics
b. Indirect: will also block reabsorption of bicarb which will cause a metabolic acidosis
What would be the tubular fluid osmolality at the end of the early PT
At this point in the early PT, you are still absorbing water with the solutes which maintains the osmolarity. So, it is iso-osmotic.
What would happen to Ca2+ reabsorption when Na+ reabsorption is inhibited by volume expansion?
- The mechanism is not well explained but Ca2+ reabsorption is very tightly coupled with Na+ reabsorption. So there will be a lot of Ca2+ reabsorption here as well.
- So when Na+ reabsorption is inhibited, so is Ca2+ reabsorption
transporters and channels in the apical and basolateral membranes of the late PT.
- a. Na+-H+ exchanger–> apical
- b. Cl-Base- exchanger–> apical
- c. Na+-K+ ATPase–> basolateral
- d. Cl- channels–> bsolateral
Overview of what is happening in the late PT
Sodium is being pumped into the blood by Na+/K+ ATPase which is creating a concentration of sodium inside the cell. This concentration gradient drives the exchange of Na+/H+ on the apical side. The base/Cl- exchanger can include bicarb as the base… or other bases like lactate. Ultimately, sodium and chloride are reabsorbed.
Which electrolyte concentration is high in the late PT and why?
- Chloride concentration is high in the lumen
How are Na+ and Cl- ions reabsorbed in the late proximal tubule?
- The Na+/K+ ATPase and Cl- channel allow for low intracellular concentration of Na+ and Cl- in the cell. This drives the Na+/H+ exchanger and Cl-/Base exchanger on the apical side.
- Na+ and Cl- are ultimately reabsorbed.
Transporters in the thin descending limb of LOH
- what is being transported?
- only H2O
What would happen to the tubular fluid osmolality at the end of the thin descending limb and why?
It would become hypertonic in the lumen because the water is leaving the lumen and entering the blood for reabsorption which means the solutes are being left behind.
Transporters on thick ascending limb
- apical side
- basolateral side
- Apical: Sodium Potassium 2 Cl cotransporter and Potassium channels
- basolateral: Na K ATPase pump, Potassium & Chloride channels
How are Ca & Mg ions reabsorbed in the thick ascending limb
- Through the paracellular pathway bc of the lumen positive potential created by the recycling of K ions
what do the Na K ATPase pump transports do in the thick acending limb of LOH
transports Na ion into the blood & creates a concentration gradient there so that Na is reabsorbed from the luminal side & 1 Na is being reabsorbed by the Na K 2 Cl co transporter transports K ions & Cl ions as well
What happens with K in the thick ascending limb
• K+ ions are being pumped into the cell by both the Na,K ATPase pump & the Na K 2Cl cotransporter
○ These K ions are recycled back into the lumen, creating positive potential in the lumen and repelling other positive ions across the paracellular pathway into the blood
Where does Thiazide act?
- why would it cause hypercalcemia?
- can PTH help?
- The NaCl channels on the distal convoluted tubule
- NaCl transporter is blocked, so that will cause a decrease in the sodium concentration inside the cell -> inactivates the Na Ca exchanger & there will be more calcium in the blood
- yes, it will act on the Ca/Na exchangers in the early distal convoluted tubule
If a medication causes urinary concentration of Na and pH to decrease while K increases
- what cell would it be effecting?
- explain the action of the hormone that has similar effects
- Principle cells
- Aldosterone
Major transporters in the late distal and collecting tubules
- Principal cells
- alpha intercalated cells
- beta intercalated cells
- Apical side: Na channels, K channels, Water channels; basolateral side: NaK ATPase
- Apical side: Hydrogen ATPase, Hydrogen Potassium ATPase; Basolateral side: Bicarb Cl exchanger
- Apical side: Chloride Bicarbonate exchange; Basolateral side: Proton pump
Effects of ADH
- kind of receptors
Increases the amount of aquaporin 2 so increases the water in the cell
- V2 receptors on the basolateral membrane & that incorporates 2 channels & those channels are incorporated into apical side of the cell
Effects of Aldosterone
- acts on?
- what does it do?
- kind of hormone; which gives it what?
- principal cells
- Goes in & works on the nucleus & increases transcription of the protein the ENaC Channels, and other things that will help the Na reabsorb
- steroid hormone; enter into the cell & they have receptors inside the cell in the nucleus, so thereby phosphorylating those proteins & increasing their transcription it increases input Na channels & K channels & those are incorporated into the apical membrane by the action of aldosterone
Potassium sparing diuretic
- direct & indirect effects of this diuretic
- compensation mech
- what happens to water?
- example
- You block the ENaC channels which increases Na reabsorption
- You’ll start using the Na/K-ATPase in order to create that concentration gradient & that will drive potassium out of the cell into the lumen & Na inside the cell
- Na reabsorption is less ->water reabsorption is also less
- amiloride
In the presence of ADH, most of the water filtered by the kidneys is reabsorbed most likely in which segments of the nephron? Why?
- PCT
- Irrespective of the presence or absence of ADH, maximum water absorption occurs in the proximal tubule
Where does most magnesium get reabsorbed?
- Most of magnesium reabsorption occurs in the thick ascending LOH
Which segment of the nephron is called concentrating segment and why?
Thin descending limb;
Permeable to water only, doesn’t allow reabsorption of solutes
Which segment of the nephron is called the diluting segment? Why?
Thick ascending limb;
Only solutes reabsorbed, no water
Explain how the concentration and diluting segments of the nephron maintain the medullary osmotic gradient
You have active transport of sodium in loop of Henle and a counter current of water in the vasa recta, and the recycling of urea maintains the balance
Difference between a cortical nepron and a juxtamedullary nephron
- juxtamedullary nephron goes into the medulla while a Cortical nephron doesn’t go into medulla
Sites of action of diuretics - Acetazolamide 2-Mannitol 3-Loop diuretic 4-Thiazide 5-potassium sparing diuretic, 6-ADH antagonist
- carbonic anhydrase inhibitor
- osmotic diuretic
- prevent reabsorption of predominantly sodium -> Magnesium and calcium stays in lumen bc positive lumen potential is not created
- Retains sodium in lumen causing calcium reabsorption increase
- aldosterone antagonist
- antagonizes ADH
Angiotensin II effect on kidney
- ^ NA-H excahnge in PCT
^ Na-Cl cotransport in DCT
PTH effect on kidney
- decreases PO4 reabsorption in PCT and ^ Ca reabsorption in DCT
ANP effect on kidney
- decrease Na reabsorption in TAL and collecting ducts
- Inhibit AT II -> decreases Na reabsorption in DCT
Aldosterone effect on kidney
- ^ apical Na channels in principal cells -> ^ Na reabsorption
- ^ K channels in principal cells -> ^ K secretion
- ^ apical H+ ATP-ase in a-intercalated cell -> H+ secretion
ADH effect on kidney
- ^ apical Na-K-2 Cl cotransporter and basolateral Na-k ATPase activites -> ^ reabsorption of Na, K, Cl, Ca, Mg
- ^ number of AQP2 channels -> ^ H2O absorption
What is glucosuria?
- other name
- Glucose in the urine
- Can also be called glycosuria
When would you see glucose in the urine?
- why that value?
- When serum glucose is over 200 mg/dL
- It is max amount of glucose that can be reabsorbed by kidney
Role of kidneys in maintenance of normal glucose homeostasis.
Maintaining normal blood glucose at 80-100 mg/dL which equate to 5.5 mmol/d
How does kidney maintain this blood glucose level?
Reabsorption of glucose and synthesis of glucose
Reabsorption of glucose
- how does this happen?
○ It filters glucose out of the blood into the filtrate in the glomerulus and then it should be 100% reabsorbed into blood plasma
Gluconeogenesis in the kidney
- when?
- substrate used
- only during extreme fasting state
- glutamine
Site for glucose reabsorption in the kidney tubule- which part of nephron?
- How?
- Early proximal convoluted tubule (majority) and some in late proximal convoluted tubule
- There is a co-transporter for Na and Glucose (SGLT1 and SGLT2) on apical side of tubular cell and on basolateral side there are Glut 1 and 2 allowing for transport of glucose from the tubular cell into the blood
What is the primary process to reabsorb glucose from the glomerular filtrate into the tubule cell?
- specifics
- how is gradient kept?
- Secondary active transport
- Na follows its gradient and brings glucose (against its concentration gradient) along with it -> Na is moving with its gradient and pulls glucose against its concentration gradient into the cell.
- Na is high in concentration on outside of cell and low inside of cell -> This concentration is kept because of the Na/K ATPase on the basolateral side of the tubular cell
Compare and contrast SGLT2 and SGLT1
- Similarities
- Differences (capacity vs affinity)
- Both absorb glucose
- SGLT2: high capacity, low affinity transporter; SGLT1: low capacity, high affinity transporter
Why does SGLT2 have low affinity (higher Km)?
The glomerular filtrate at that point has a lot of glucose so you do not need high affinity
Why does SGLT2 have high affinity (higher Km)?
In distal part of proximal convoluted tubule 98% has already been reabsorbed, less amount of glucose in the filtrate, so you would need high affinity transporter in order to bind glucose
How is intracellular Na gradient maintained?
- Na/K ATPase on basolateral side of tubular cell
What is the role of GLUT transporter?
- where are they located?
- kind of diffusion and why?
- to take glucose from the cell into the blood
- basolateral side of cell
- facilitated diffusion because glucose needs a transporter or channel in order to get across the membrane
Explain relation between filtration load, resorption load and secretion load
- reabsorption rate and filtration rate
- excretion
- Re-absorption rate will follow filtration rate as long as its under the transport maximum (200). Once glucose goes over threshold (200) then you will have more glucose in the filtrate. Resorption and filtration are very balanced with normal blood level
- In normal patient the plasma blood glucose is 80-100 mg/dL so resorption and filtration is balance, and whatever is filtered is reabsorbed back. And we do not see green line because there is no excretion of glucose in the urine.
What happens to reabsorption and filtration rate in diabetic
- You start to hit the splay portion on the graph because SGLT transporters are saturated at that point and you start to have urine excreted in the urine because the kidney cannot reabsorb that much glucose
What happens to excretion with diabetics?
Because 200 mg/dL is the renal threshold, so just above that the filtration and reabsorption is no longer balanced so you would see some glucose left in glomerular filtrate and may see it in urine.
Do all diabetics with sugar above 200 have glycosuria?
- No, because it is very small so it takes a while to appear in the urine.
When would you definitely have glycosuria
round 400, because 400 is transport maximum
SGLT2 inhibitors
- what line of treatment
- what type of patient is this used for?
- how to tell?
- effect of drug
- risk
- 3rd line for diabetics
- patients with potential of heart failure because of the extreme diuresis that goes along with this medication
- look for “liflozin” for generic
- you would have increase of glucose in urine to be excreted
- sometimes have increased risk for UTI because of increased glucose excretion
Pt brought to ER with light-headedness and near syncope after working outside on hot summer day. Normal urine output, glucosuria, and HbA1C of 4.8
- ddx?
- actual dx
- kidney function
- well controlled diabetes, rhabdomyolysis, kidney injury due to aminoglycoside
- Familial renal glucosuria; the glycosuria is just incidental finding
- kidney function is normal the only thing affected is dysfunctional transporters specifically SGLT2
If SGLT1 is affected what would pt present with?
- SGLT1 is expressed in gut and transports glucose AND galactose
- Pt would have diarrhea and acidosis because of decreased galactose
- This would also be more present in infantile stage
Could dehydration alone cause glucosuria?
Dehydration alone would not give glucosuria, only if there was already damage to the proximal tubule.
Will the threshold for glucose always decrease in pts with familial renal glucosuria?
Probably not because familial renal glucosuria can be caused by different mutations so if a mutation affects the efficiency of SGLT2 then the number of transporters are the same but the efficiency is less so they might saturate easier which would cause the threshold to fall. However, if the mutation affects the amount of transporters and there are less but they are still as efficient as normal transporters then you will have normal threshold.
Labs that would be consistent with AKI?
relative increase in her creatinine & a relative decrease in her glomerular function.
How to distinguish a prerenal vs intrinsic vs post renal AKI?
- Use fractional excretion of sodium.
- If it is greater than 1% it is intrinsic
What medication can impact the Fractional Excretion of Na+
- what would you use instead
- use of the hydrochlorothiazide renders the FENA ineffective for determining if she was a prerenal vs intrinsic AKI
- calculate the FE of urea
How to calculate the FE of urea
(serum creatinine * Urine urea)/(serum urea * urine creatinine); If it is less than 35% you have a prerenal AKI & if it is greater than 35% you have an intrinsic AKI
What is BUN?
- where is it synthesized?
- In AA metabolism; The amine group is toxic so it gets converted to urea.
- Happens exclusively in the liver and gets eliminated through urine
How the kidney handles urea under normal circumstances
- reabsorption location
- absorbed from the blood by the kidney, most of it is excreted but some of it is reabsorbed and put into the interstitium of the medulla so that it can help to drive water out of the descending LOH
- primarily in the PCT and in the collecting duct
- as it is cycled, the remaining urea no longer wanted is secreted back into the descending thin loop of Henle and 40% is excreted in the urine
What is the main mechanism of urea reabsorption?
how?
- what about in the collecting tubule? how?
- simple diffusion, flows dows its concentration gradient
- There is a lot of water reabsorption going on in the PCT which makes the urea very concentrated in the tubular fluid and that drives the passive diffusion into the interstitial space
- facilitated diffusion using UT1 (apical side) & UT3 (on basolateral side). Water is reabsorbed from collecting duct with help of ADH, removal of water increases concentration gradient in tubular fluid which drives for reabsorption of urea into interstitium
Regulation of Urea reabsorption in the collecting duct
- why?
- ADH
- ADH is used to reabsorb water -> that would concentrate Urea in the tubule-> also binds to UTA1 and 3 -> more Urea reabsorbed
What drives the secretion of urea in the loop of Henle?
- The concentration gradient that is built by the reabsorption
- More reabsorption occurs in the PCT and the IMCD –> it builds up the medullary concentration gradient and that leads to the secretion of flow of urea down its concentration gradient from the interstitium into the tubular fluid bc you don’t want to retain too much of it bc it is toxic. You just wanna retain just enough to maintain the concentration gradient
So now it should be clear why it reabsorbs, secretes, reabsorbs
What would happen to urea retention in dehydrated person?
low urine flow, more water retention, more urea retention, less urea elimination
What would you use to treat cellulitis in patient that had gout and is on probenecid?
- what is the major problem with anti-biotics and this drug
- what antibiotic could you use?
Probenecid uses OAT transporter to get into proximal tubule to be excreted, this is a common mechanism of transport into the tubule by multiple medications, including penicillin, cephalosporins, and methotrexate, and aspirin. Since the medications would be competing to use the same transporter you could get to toxic level of build up in the blood, and neither of the drugs would work effectively.
- you could use clindamycin because it’s a lincosamide and not a beta lactam
A patient that has been prescribed Probenecid to better manage his gout, is prescribed a loop diuretic to manage their heart failure. Predict the effect of combing probenecid with a loop diuretic.
- Probenecid acts primarily where?
- Within the proximal tubule; reduces the secretion of loop diuretics because loop diuretics also require the use of these OAT1 and OAT3 transporters in the proximal tubule to enter the tubule to get into loop of henle and be able to do their job
- decrease renal clearance -> increase half life -> elevates plasma concentration
Why must med dosages be changed for patients who are
- elderly
- obese
- when you have someone that’s elderly, you have reduced muscle mass -> would have decreased volume of distribution so loading dose should be reduced
- Volume of distribution of obese patient is increased so the dose need to be increased in order to be effective.
Half life equation
= (0.7* volume of distribution)/ clearance
How to calculate apparent volume of distribution
- why is it called that?
- amount of drug in body/ concentration in the blood
- not really what it looks like. but when you calculate volume of distribution its greater that the physical volume of the system.
Clearance
- what is it?
- dependent on?
- combination or total of all of the organs involved in elimination of the durg
- rate of elimination: made up of excretion and metabolism of the drug
What is half-life?
- Time with which it takes to reduce the drug concentration by 50%
- When looking at graph pick a random point of a serum concentration, then pick a point that was half of that (so if 8 was pick, then 2nd point is 4) and then subtract the times at which that concentration was taken from eachother, and that should give you the half life.
What’s a drug steady state?
When elimination and accumulation are in equilibrium
If you were do give the dose orally, would you be able to maintain a steady state very easily?
○ No, because you’re going to have this variable concentration that’s less reliable than a constant infusion, because of metabolism and first-pass effect distribution
rule of thumb when relating % steady state to half-life
○ 1 half-life is always going to be 50% steady state
○ 2 half-lives is always going to be 75% steady state
- 3 half-lives is always going to be about 87%
○ 4 or 5 half-lives is always going to be anything that’s above 90%
○ Key Point: When you get to 4 and 5 half-lives, you’re at steady state
- When we’re dosing medications, like in Katzung it says half-life 4-6 hours, how does achieving a steady state factor into our dosage measurements?
- It would take 4 to 5 half-lives for that drug to get to a steady state in that person’s body. Since one half life is 4-6 hours, you’d calculate 4-6hours x 4 or 5 , and that would equal how long it takes to get to steady state. You multiply the drug half-life by whatever steady state you need to get to.
- Similarly, you wouldn’t have a full maximal concentration in the blood once you’re infusing until 4 to 5 half lives. The constant concentration that you’re looking for will be at 4 to 5 half lives consistently.
What is aminoaciduria?
- normal?
- how are they reabsorbed?
- dx?
- rash?
- insomnia
- balance and neuro sxs
- AA’s in the urine
- no, usually 100% is reabsorbed
- cotransporters and use the Na+ gradient or H+ ion gradient for reabsorption
- Hartnup disease; where the transporter that reabsorbs ring structured/aromatic AA’s is defective
- patients show deficiency in Trp and would eventually end up with a deficiency of Vit B3. This why the patient is showing signs of skin rashes - classic presentation of B3 deficiency
- Trp makes serotonin, the precursor of melatonin, and melatonin contributes to sleep which could be causing insomnia;
- Vit B3 function -> NAD+ and NADH; Used for glucose utilization, which would go down in this case -> Neurons heavily rely on glucose utilization, which can contribute to loss of balance
